Glucocorticoid-Induced Synaptic Scaffolding Deficits and Hippocampal-Prefrontal Dysregulation in the Progression of Mood Disorders

Background: Bipolar disorder (BD) is frequently preceded by major depressive disorder (MDD), yet the neurobiological mechanisms underlying this transition remain insufficiently understood. Objective: This paper proposes a mechanistic model linking chronic stress, glucocorticoid (GC) exposure, and synaptic alterations to the progression from MDD to BD. Methods: We review evidence suggesting that GC-induced downregulation of synaptic scaffolding proteins (e.g., PSD-95) impairs hippocampal integrity, weakens hypothalamic–pituitary–adrenal (HPA) axis feedback regulation, and contributes to glutamate dysregulation and NMDA receptor overactivation. Inflammatory signaling triggered by microglial activation further promotes maladaptive synaptic pruning, particularly within hippocampal–prefrontal circuits. Results: These neurobiological alterations form a pathological cascade—scaffold loss, excitotoxicity, glial dysfunction, and circuit disintegration—which may gradually alter the cognitive and affective profile of individuals with MDD, increasing vulnerability to a bipolar trajectory. Conclusion: This model provides an integrative framework for understanding neuroprogression in mood disorders and highlights potential biomarkers and intervention targets for early-stage diagnosis and treatment.